A specific deletion on chromosome 22 (22q11.2 deletion syndrome or 22q11.2DS) is known to cause cognitive dysfunction and put individuals at greater risk for developing schizophrenia—particularly because of that deletion’s effect on the cathechol-O-methyltransferase (COMT) gene located in that region. In a study published March 2014 in Biological Psychiatry, a team of researchers led by Daniel R. Weinberger, M.D., Director and CEO of the Lieber Institute for Brain Development (LIBD), has started to piece together a picture that shows how a co-occurrence of multiple variants of COMT that appear to cause few problems in isolation work in tandem to create the overall deficiencies.
A common variant of COMT, known as the val/Met polymorphism, has been previously linked to working memory deficits and issues with emotional regulation—functions modulated by the human prefrontal cortex—but despite numerous attempts to identify the causal mechanism results have remained inconclusive. The researchers in this study looked more closely at individuals with the Met (vs. Val) allele and investigated other carefully selected COMT variants (those previously reported to be linked to COMT biology and prefrontal cortex function), as well as “epigenetic” changes—chemical processes initiated by environmental impacts that alter gene expression—that might also alter the gene’s activity.
The researchers conclude that numerous genetic factors thus influence the risks associated with carrying this micro-deletion on chromosome 22 and that single variant studies are insufficient to yield conclusive results.
The research team worked with tissue samples from 53 individuals with the 22q11.2DS from the Behavioral Neurogenetics Center in Israel and typically developing control subjects of European ancestry without the deletion from samples at the National Institutes of Mental Health (NIMH). This deletion offers a good test case because affected individuals still carry one copy of the genes that have been lost. Subjects ranged in age from 13 to 32 years. Twenty-nine individuals with the deletion were Met allele carriers. Another 14 had a psychotic disorder and were divided evenly among Met and Val allele carriers.
The scientists tested the following hypotheses: that individuals with 22q11.2DS would have approximately 50% less COMT gene expression, protein levels, and enzyme activity; that there would be significant effects of other COMT variants on prefrontal cognitive functioning; and that combinations of variants of COMT would alter the associations seen with the Val/Met variant alone.
As anticipated, they found that individuals with 22q11.2DS showed a 50 percent reduction in the expression of proteins produced by COMT. Moreover, the team showed that the interaction of the other previously reported COMT risk variants they studied were critical for creating the COMT-associated risk for cognitive dysfunction and psychosis. In particular, Val allele carriers with the A allele of a genetic region known as rs165599 showed strong COMT activity. Those with low COMT activity and at greatest risk for cognitive and psychiatric illness, even compared to carriers of the Met allele, were individuals who tested positive for both the Val and G alleles.
Unlike previous studies, the researchers here found no deleterious effects associated with uniquely carrying the Met allele. What’s more, even low COMT activity alone—as seen in Val and A allele carriers—does not appear to increase one’s risk of developing psychosis. The researchers conclude that numerous genetic factors thus influence the risks associated with carrying this micro-deletion on chromosome 22 and that single variant studies are insufficient to yield conclusive results.